Induction of human γ globin gene expression by histone deacetylase inhibitors
Induction of human γ globin gene expression by histone deacetylase inhibitors
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DOI：
10.1182/blood-2003-02-0478
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发表时间：
2004-01-15
期刊：
影响因子：
20.3
通讯作者：
Jung, M
中科院分区：
文献类型：
--
作者：
Cao, H;Stamatoyannopoulos, G;Jung, M
我们研究了3类组蛋白去乙酰化酶抑制剂对人γ-珠蛋白基因活性的诱导作用：A型组蛋白去乙酰化酶抑制剂的酰胺类似物、Trapoxin的异羟肟酸类似物和Scriptaid及其类似物。筛选包括通过使用稳定转染有含有与萤火虫荧光素酶连接的γ启动子和与海肾荧光素酶连接的β启动子的构建体的GM 979细胞的培养物来测量这些化合物对γ和β人类基因启动子活性的影响。属于所有3类的化合物在低微摩尔浓度的筛选测定中诱导γ基因启动子活性。组蛋白去乙酰化酶（HDAC）抑制剂增加组蛋白H4的乙酰化，并诱导内源性小鼠胚胎基因的表达。他们还增加了γ mRNA的水平和含胎儿血红蛋白的成红细胞在红系爆发形成单位（BFUe）培养健康成人个体的频率。在HDAC酶测定中显示出非常相似的HDAC活性抑制程度的化合物在它们对γ基因启动子活性的影响上显著不同，提高了与γ珠蛋白基因染色质相互作用的HDAC的选择性的可能性。
We investigated the induction of human gamma globin gene activity by 3 classes of histone deacetylase inhibitors: amide analogues of trichostatin A, hydroxamic acid analogues of trapoxin, and scriptaid and its analogues. The screening consisted of measuring the effects of these compounds on gamma and beta human gene promoter activity by using cultures of GM979 cells stably transfected with a construct containing a gamma promoter linked to firefly luciferase and a beta promoter linked to renilla luciferase. Compounds belonging to all 3 classes induced gamma gene promoter activity in the screening assay in low micromolar concentrations. Histone deacetylase (HDAC) inhibitors increased acetylation of histone H4 and induced the expression of endogenous murine embryonic genes. They also increased the levels of gamma mRNA and the frequency of fetal hemoglobin-containing erythroblasts in erythroid burst-forming unit (BFUe) cultures from healthy adult individuals. Compounds that displayed very similar degrees of inhibition of the HDAC activity in an HDAC enzymatic assay differed strikingly on their effects on gamma gene promoter activity, raising the possibility of selectivity of HDACs that interact with the gamma globin gene chromatin.